Skeletal muscle and peripheral nerve regenerate more poorly in old than in young rats. On the basis of data obtained from cross-age grafting models, an age-related change in the host appears to impair the capacity of muscle and nerve to regenerate. The Specific Aims of this Program Project are to test four Group Hypotheses that in old as compared with young rats: A. poor regeneration of muscle grafts is related to deficient reinnervation; B. no structural or functional differences exist in muscle fibers during an early preinnervation stage, but structure and function of muscle fibers and motor units are impaired during a postinnervation stage; C. impaired axonal regeneration is related to defects in neuronal gene expression, myelin clearance, and macrophage and Schwann cell function; and D. cross-age nerve grafts ultimately become adapted to characteristics of the host. Hypotheses A and B will be tested by physiological analysis of single muscle fiber, motor unit and whole muscle properties, histochemistry and nerve staining, and electron microscopy. Hypotheses C and D will be tested by immunocytochemistry, in situ hybridization, morphometric analysis, autoradiography, growth factor analysis and Northern and Western blotting. The significance of the proposed research is the clarification of the mechanisms responsible for the improvement of muscle and nerve regeneration in old animals. The long-term goal of this research is to provide the basis for improving the repair of damaged muscle and nerve in old individuals.